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Arch Dis Child: first published as 10.1136/adc.62.4.385 on 1 April 1987. Downloaded from

Archives of Disease in Childhood, 1987, 62, 385-391

Central nervous system dysfunction and erythrocyte triphosphate depletion in phosphorylase deficiency

H A SIMMONDS, L D FAIRBANKS, G S MORRIS, G MORGAN, A R WATSON, P TIMMS, AND B SINGH Purine Laboratory, Guy's Hospital, London, Department of Immunology, Institute of Child Health, London, Department of Paediatrics, City Hospital, Nottingham, Department of Paediatrics and Chemical Pathology, National Guard King Khalid Hospital, Jeddah, Saudi Arabia

SUMMARY Developmental retardation was a prominent clinical feature in six infants from three kindreds deficient in the purine nucleoside phosphorylase (PNP) and was present before development of T immunodeficiency. (GTP) depletion was noted in the erythrocytes of all surviving homozygotes and was of equivalent magnitude to that found in the Lesch-Nyhan syndrome (complete - phosphoribosyltransferase (HGPRT) deficiency). The similarity between the neurological complications in both disorders that the two major clinical consequences of complete PNP deficiency have differing

indicates copyright. aetiologies: (1) neurological effects resulting from deficiency of the PNP enzyme products, which are the substrates for HGPRT, leading to functional deficiency of this enzyme. (2) immunodeficiency caused by accumulation of the PNP enzyme substrates, one of which, , is toxic to T cells. These studies show the need to consider PNP deficiency (suggested by the finding of hypouricaemia) in patients with neurological dysfunction, as well as in T cell immunodeficiency. http://adc.bmj.com/ They suggest an important role for GTP in normal central nervous system function.

Deficiency of the enzyme purine nucleoside phos- findings in our latest case of PNP deficiency with phorylase (PNP:EC 2.4.2.1) was first reported in those in two previous kindreds5 9 and highlights 1975 in a child with recurrent and severe developmental retardation as a prominent on September 29, 2021 by guest. Protected anaemia.' Clinical features in the first nine cases2-4 clinical feature of the disorder. We have also found have invariably been related to a pronounced severe guanosine triphosphate (GTP) depletion in reduction in T cell numbers and function, with the red cells of all available homozygotes from these either normal or enhanced B cell function.17 kindreds,5 9 1lin addition to the dGTP accumula- Deoxyguanosine triphosphate (dGTP) has been tion noted earlier by others.2-4 As the brain has a found in the erythrocytes and implicated in the T high requirement for GTP 12 and resembles the cell dysfunction of the disorder.2-5 The age at human erythrocyte (Fig. 1) in being largely depen- presentation has varied from birth to 6 years. dent on salvage to maintain GTP concentrations the Therapeutic approaches to restore immune com- combined clinical and biochemical findings support petence have usually been unsuccessful.2-5 Most a direct relation between the enzyme defect and the patients have died from viral infection or neurological dysfunction. They underline the fact lymphoma. 1-9 Successful engraftment after haploid- that PNP deficiency should be suspected in children entical bone marrow transplantation has been with central nervous system (CNS) disorders as well reported recently in a single case.") as T cell immunodeficiency and suggest a metabolic This paper compares clinical and biochemical basis for this association. 385 Arch Dis Child: first published as 10.1136/adc.62.4.385 on 1 April 1987. Downloaded from

386 Simmonds, Fairbanks, Morris, Morgan, Watson, Timms, and Singh

DNA ;

d-Guanosine dGDP GDP ADP

d- d- Adenosine dGMP G MP IMP * AMP

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Plasman ' S, ,fl s , d-Inosine d-Guanosine Guanosine Inosine Urine Fig. 1 Pathways of purine , indicating the importance of PNP for the degradation of derived from the turnover of DNA, as well as arising from A TP and GTP (all shown in bold) during daily cell turnover. In the absence of PNP (broken arrows) the four PNP substrates indicated accumulate in the plasma and are excreted in urine in place of . The potential for dGTP formation after deoxyguanosine accumulation when PNP is defective is also shown. The effect of complete PNP deficiency in restricting substrate availability for HGPRT is evident from the broken line, copyright. showing that HGPRT normally plays a vital role in tandem with PNP for guanine recycling and maintenance of GTP concentrations, particularly when de novo synthesis is absent, as in the human erythrocyte, or limited, as in the brain. The importance of extracellular adenosine, and hence adenosine , for maintaining A TP concentrations in the red cell, due to a lack of the normal route of A TP formation from IMP present in nucleated cells, is also indicated.

PNP=Purine nucleoside phosphorylase; DNA=deoxyribonucleic acid; ATP=; ADP=; AMP= ; GTP=guanosine triphosphate; GDP=; GMP=; dGTP=deoxyguanosine triphosphate; dGDP=deoxyguanosine diphosphate; dGMP- deoxyguanosine monophosphate; HGPRT=hypoxanthine-guanine phosphoribosyltransferase; IMP=inosine http://adc.bmj.com/ monophosphate; d-=deoxy.

Patients and methods the progressive immunodeficiency.5 Excessive head lag and irritability were noticeable by 3 months. Case reports. Extensive neurological investigation revealed no Family I organic lesion or viral infection. The infant there- The propositus (case 1) in this family was the first after remained profoundly hypotonic with develop- on September 29, 2021 by guest. Protected son of healthy Irish parents who were fourth mental delay in all spheres. Hypertonicity of the cousins. A full clinical history has been reported.8 In lower limbs developed before his death at 2 years brief, the infant had considerable developmental from an acute para-influenza type 111 infection with delay before an aseptic meningitis at 2 years, from pneumonia. There was no structural brain lesion at which he made a full recovery. At 2 years 8 months postmortem examination. he presented with an illness similar to glandular fever. He was unable to walk unsupported and had a Family 2 crude hand grasp and delayed speech. A spastic The propositus (case 3) was an Arab girl, the sixth tetraparesis was clinically evident. He died of child of parents who were first cousins. Full details malignant lymphoma of the immunoblastic type are given elsewhere.9 She presented with anaemia of shortly after PNP deficiency was defined. seven days' duration at 4 years in January 1985. A A second boy (case 2) was born in June 1980 and spastic tetraparesis was noted. Developmental delay PNP deficiency was confirmed at birth. He was kept was first investigated at 1 year. General physical under close clinical observation while different examination showed hypertonia and exaggerated treatments were given in an attempt to ameliorate tendon reflexes, involving all limbs. An intention Arch Dis Child: first published as 10.1136/adc.62.4.385 on 1 April 1987. Downloaded from

Central nervous system dysfunction in purine nucleoside phosphorylase deficiency 387 tremor was also present. There was severe develop- red cells were determined using a Waters (Millipore- mental retardation, with motor involvement (equal Waters, Harrow, Middlesex, England) trimodule to a child of 1 year) being more severe than fully automated high pressure liquid chromato- intellectual development (equivalent to a child of graphy system coupled to a 5[t APS-Hypersil 2-5 years). The child had started to sit at 1 year and column, or a 5 Spherisorb ODSI column stand at 3 years and walked unsteadily on tiptoe with (25 cm x 4.9 mm, Hichrom, United Kingdom), for help at 3 years 9 months. Investigations showed a the separation of , or and child with anaemia with a positive result of a direct bases, respectively." 13-15 The method used for Coombs test and severe T cell immunodeficiency.9 determination of PNP activities, as well as the activ- A computed tomogram of the brain and electro- ity of the other purine -namely, adenosine encephalogram yielded normal results. The child deaminase, phosphoribosyltransferase, and subsequently succumbed to viral infection at the age hypoxanthine-guanine phosphoribosyltransferase of 4 years 6 months. Permission for postmortem (HGPRT)-in lysed red cells using high pressure examination was refused. liquid chromatography, has also been reported.'4 Family history revealed an elder sister (case 4) Studies with 8-[14C] labelled deoxyguanosine, using who had died at 4 years of chickenpox complicated intact red cells, were also carried out to exclude the by pneumonia and carditis and had also been possibility of a labile enzyme detectable only in severely developmentally retarded and suffered intact cells (not lysed cells). They were processed repeated chest and ear . (She was con- using a radiodetector (Reeve Analytical, Glasgow, sidered a homozygote for PNP deficiency from the Scotland) coupled to the above high pressure liquid similarity in the case history). An 11 month old chromatography system as previously described.'5 brother (case 5) showed similar abnormalities to the S-adenosylhomocysteine hydrolase activity was propositus: CNS involvement was evident from poor determined by the method of Kaminska and head control, generalised hypotonia with inability to Fox.16 stand, and a delay in fine motor milestones. Only limited investigations were permitted, but retarda- Results copyright. tion remains the principal problem. Despite the severe T cell immunodeficiency,9 there have been Purine enzymes. The propositus in family 3 (case 6) no episodes of infection over the past 12 months. was found to lack any detectable PNP activity in lysed erythrocytes, as previously found for cases 2, Family 3 3, and 5 (Table 1). Completeness of the enzyme The propositus in this new kindred (case 6) was the defect and exclusion of the presence of a labile fourth child of healthy, unrelated parents. One child enzyme was confirmed by incubation of intact red http://adc.bmj.com/ had died at birth. The two surviving siblings are cells from case 6 with 8-[14C] deoxyguanosine. healthy. He was noted to have mild left hemiparesis (This showed no metabolism of substrate to and delayed motor development aged 14 months guanine, although detectable amounts of deoxy- and at the time of study was attending a special guanosine triphosphate were formed. Results not school. He presented in March 1986 at the age of 4 shown.) Both parents and one sibling in family 3 years 5 months with Coombs positive autoimmune showed heterozygote PNP activities in lysed red haemolytic anaemia (haemoglobin 8-9 g/dl) and cells (Table 1). The results are in accordance with thrombocytopenia (18x109/1) after the latest of a the recessive mode of inheritance reported in the on September 29, 2021 by guest. Protected series of pulmonary infections. He was shown to disorder.2-4 8 have severe T cell deficiency with lymphopenia and The presence of normal HGPRT activity in case lack of mitogen and alloantigen responses; im- 6 (Table 1), as in cases 2, 3, and 5, was munoglobulin concentrations were normal (IgG 8-9, also confirmed by studies in intact red cells (results IgA 051, and IgM 1-1 g/l). At this time he was not shown). Of the other purine enzymes, both making reasonable developmental progress, with adenine phosphoribosyltransferase and adenosine the non-progressive hemiparetic cerebral palsy as deaminase were again raised in case 6 (Table 1), a his only neurodevelopmental problem. He died at 4 finding noted in some but not all homozygotes.' 9 years 6 months of complications related to immuno- Low S-adenosylhomocysteine hydrolase activities suppression of graft versus host disease contracted (patient range 1*7-3-0 nmol/mg Hb/h: control range from a transfusion. Permission for postmor- 3-69-0 nmol/mg Hb/h) were also found, as reported tem examination was refused. earlier by others in this disorder.> 9 16 Extremely low activities of this enzyme were first noted in Biochemical methods. Purine nucleoside concen- deficiency, the companion trations in plasma and urine and nucleotides in purine disorder presenting as severe combined Arch Dis Child: first published as 10.1136/adc.62.4.385 on 1 April 1987. Downloaded from

388 Simmonds, Fairbanks, Morris, Morgan, Watson, Timms, and Singh Table 1 Specific activities offour different purine enzymes in the parents and the surviving siblings in family 3, compared with previous results in cases 2, 3, and 5.5 9 Plasma and urine purine concentrations in the four homozygotes show the accumulation of the four nucleosides inosine, guanosine, deoxyinosine, and deoxyguanosine in place of uric acid

Purine enzyme activity in lysed erythrocytes (nmollmg Hblh) PNP ADA APRT HGPRT Family 3 Case 6 <01 108 70 194 Sister 4668 65 25 152 Brother 1940 99 25 139 Father 1988 65 19 134 Mother 2367 93 33 154 Family 1 Case 2 <0-1 62 45 111 Family 2 Case 3 <0-1 185 67 138 Case 5 <0-1 117 42 160 Control (n=200) Mean 4500 70 24 105 (SD) (722) (12) (4.8) (16.5) Purine concentrations in body fluids Case Plasma (,molll) Urine (mmollmmol) No Uric acid Inosine Guanosine Deoxyinosine Deoxyguanosine Uric acid Inosine Guanosine Deoxyinosine Deoxyguanosine 6 T 62 23 19 14 T 1.10 0-36 0-36 0-29 2 7 46 9 2 2 T 1-68 0 57 0-32 0-29 3 T 41 11 7 6 T 1.90 0-87 0-38 0.41 5 5 49 13 6 5 T 1-44 0-74 0-41 0-33 Control - - - - range (130-230) (0-2-1.0) copyright. PNP=Purine nucleoside phosphorylase: ADA=adenosine deaminase; APRT=adenine phosphoribosyltransferase; HGPRT=hypoxanthine-guanine phosphoribosyltransferase. T=Trace. --Not normally detectable.

Table 2 Mean red cell concentrations in thefour homozygotes from the three PNP deficient kindreds compared http://adc.bmj.com/ with the mean values from 20 control children and seven patients with HGPRT deficiency, showing the correlation between GTP concentrations and the degree ofneurological involvement as well as the accumulation ofdGTP in PNP deficient red cells (goutlretarded=dysarthria, spastic gait, but no self mutilation)

Case Red cell nucleotides (4smolll packed cells) No ATP ADP AMP GTP GDP dGTP dGTP NAD UDPG Cases with PNP deficiency 6 1784 134 13 9 7 7 4 319 126 on September 29, 2021 by guest. Protected 2 1044 13(0 10 5 5 3 3 276 149 3 10)12 132 39 6 4 5 4 307 87 5 1569 149 12 5 4 4 5 213 110 Cases with HGPRT deficiency I * 1540 130 8 9 6 - - 193 116 2* 1813 249 13 12 10 - - 226 139 3t 1274 104 8 14 8 -- 162 87 4t 1378 91 15 16 8 -- 221 123 5: 1207 170 21 51 15 - - 140 73 6: 1125 205 4 43 12 - - 239 64 7: 1793 195 6 45 18 - - 151 105 Controls (n=20) Mean 1549 144 10 68 15 - - 72 44 (SD) (72) (47) (8) (11) (3) - - (15) (8) PNP=Purine nucleoside phosphorylase; ATP=adenosine triphosphate; ADP=adenosine diphosphate; AMP=adenosine monophosphate; GTP=guanosine triphosphate; GDP=guanosine diphosphate; dGTP=deoxyguanosine triphosphate; dGDP=deoxyguanosine diphosphate; NAD=nicotinamide adenine dinucleotide; UDPG=uridinediphosphate ; HGPRT=hypoxanthine-guanine phosphoribosyltransferase; -not normally detectable. *Lesch-Nyhan syndrome. tGout/retarded=dysarthria, spastic gait, but no self mutilation. tGoutlno neurological complications. Arch Dis Child: first published as 10.1136/adc.62.4.385 on 1 April 1987. Downloaded from

Central nervous system dysfunction in purine nucleoside phosphorylase deficiency 389 immunodeficiency,1&S but the association, if any, filtration rate for the four nucleosides indicated net with the immunodeficiency remains undefined. tubular secretion. Plasma and urine purine concentrations. Table 1 Erythrocyte nucleotide concentrations. Mean red also shows that case 6 likewise accumulated high cell nucleotide concentrations in case 6 (Table 2, concentrations of the four PNP substrates, inosine, Fig. 2) showed very low guanosine triphosphate/ guanosine, deoxyinosine, and deoxyguanosine, in guanosine diphosphate concentrations, as noted place of uric acid. The latter was virtually undetect- earlier in cases 2, 3, and 5,5 9 associated with raised able in both plasma and urine, confirming the deoxyguanosine triphosphate/deoxyguanosine diph- completeness of the enzyme defect in all the osphate, nicotinamide adenine dinucleotide, and homozygotes we studied. Excretion measured as an uridinediphosphate glucose concentrations. index of creatinine showed the purine overproduc- Mean red cell nucleotide concentrations from tion characteristic of this disorder (three- to fourfold patients with HGPRT deficiency are also shown in normal). Renal clearances relative to the glomerular Table 2 for comparison and show that red cell GTP

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Time (mins) Fig. 2 High performance liquid chromatography traces at 254 nm and 005 aufs after injection of25 p1 of extract from the red cells of case 6 (PNP-) and a case with the Lesch-Nyhan syndrome (HGPRT-), showing the severe GTP and GDP depletion compared with the control and the presence of two additional peaks corresponding to dGDP and dGTP in the PNP deficient cells. (Peak marked X in the HGPRT- cells is ZTP: 5-amino-4-imidazolecarboxamide ribotide.)

PNP=Purine nucleoside phosphorylase; HGPRT=hypoxanthine-guanine phosphoribosyltransferase; ATP=adenosine triphosphate; ADP=adenosine diphosphate; AMP=adenosine monophosphate; GTP=guanosine triphosphate; GDP=guanosine diphosphate; dGTP=deoxyguanosine triphosphate; dGDP=deoxyguanosine diphosphate; NAD=nicotinamide adenine dinucleotide; UDPG=uridinediphosphate glucose. Arch Dis Child: first published as 10.1136/adc.62.4.385 on 1 April 1987. Downloaded from

390 Simmonds, Fairbanks, Morris, Morgan, Watson, Timms, and Singh depletion was likewise'9 a characteristic of severe it has not been found in partial HGPRT deficiency HGPRT deficiency (Lesch-Nyhan syndrome) and without neurological involvement (sex linked reces- tended to reflect the severity of the CNS involve- sive gout/urolithiasis). ment. Red cell GTP depletion was not found in the These findings suggest an important link between four patients with partial HGPRT deficiency in GTP concentrations and normal CNS function. GTP whom CNS function was normal. is known to be essential both for sustained macro- molecular synthesis and neurotransmission within Discussion the CNS. Consequently, restriction of substrate supply to HGPRT, due to defective PNP activity The purpose of this report was to highlight the (Fig. 1), could be as damaging to either of these neurological abnormalities that were a prominent functions as a defect in HGPRT itself. This hypo- clinical feature in six patients from three PNP thesis is supported by the fact that the clinical deficient families. It should be emphasised, there- progress of case 2 bore many similarities to that fore, that immunodeficiency may not be the present- described for children with the Lesch-Nyhan ing symptom in this disorder. Neurological involve- syndrome, where generalised muscular hypotonia ment was also present in four of the first nine from infancy is considered to be the basic abnor- published cases, but it was questioned whether this mality on which torsion dystonia is subsequently was secondary to viral infection, possibly contracted superimposed.'2 HGPRT activity is higher in the by immunisation with live .2 Our observations CNS than in any other tissue, and in the neonatal indicate that CNS viral infection is an unlikely cause period the ratio of HGPRT salvage activity to de of the neurological deficit seen in these patients. novo synthesis increases considerably after the main Case 2 was investigated from birth and showed head burst of neuroblast and neuroglial proliferation.'2 lag and excessive irritability at 3 months. Our latest The absence of any anatomical or histopathological case had neurological problems that required lesions in the brain in the Lesch-Nyhan syndrome attendance at a special school, well before the onset suggests that the enzyme deficiency produces neuro- of autoimmune disease. Spastic tetraparesis was logical dysfunction by interfering with brain function copyright. present in three siblings from the first Dutch rather than brain morphogenesis. 12 Extensive kindred;2 3a recent Dutch case was investigated neurological investigation in case 2 also revealed no initially for spastic diplegia and behavioural dis- anatomical lesion. This was confirmed at postmor- orders, not immunodeficiency.' Furthermore, tem examination. neurological complications have not been present in The combined clinical and biochemical results any of the 12 children with adenosine deaminase suggest that CNS dysfunction in PNP deficiency is a deficiency and severe combined immunodeficiency direct consequence of the enzyme defect and relates http://adc.bmj.com/ that we have studied.'8 to an inherent inability to sustain GTP at concentra- Neurological symptoms have now been described tions essential for normal function, with the red cell, in 50% of cases with PNP deficiency. Of the as in HGPRT deficiency, reflecting a wider deficit in remainder, there has been no mention of CNS tissues, such as brain, that also depend on salvage function in five homozygotes,2 6 while mild neurolo- for maintaining GTP concentrations. Whether the gical problems associated with an intention tremor finding of GTP depletion and/or the associated were noted in one case, with a total absence of accumulation of deoxyguanosine triphosphate in neurological problems in three others.2 The four as well as red cells9 is also important for the on September 29, 2021 by guest. Protected latter cases, however, had some residual PNP immune response is unknown. With the exception of activity. Two further cases exist that have not been case 6, platelet numbers have been normal, but GTP reported in detail and apparently do not have depletion in vitro has been linked with defective neurological involvement, but again these are in the synthesis of deoxyribonucleic acid in lymphoid older age group, suggesting some residual enzyme. cells.20 As immunodeficiency is not a facet of the (Hershfield MS. Personal communication.) Thus Lesch-Nyhan syndrome, however, it would seem the range of neurological involvement apparently that GTP depletion per se is not implicated in the equates well with the severity of the enzyme gradual attrition of T cell function in PNP deficiency. deficiency. The other noteworthy finding in this In summary, this study underlines the fact that report is that severe erythrocyte GTP depletion immunodeficiency may not necessarily be the pre- seems to be characteristic of PNP deficient kindreds senting abnormality, or of the greatest immediate with neurological involvement. (Zegers BJM. concern to the family, in patients with PNP defic- Personal communication.) GTP depletion has also iency. The enzyme defect should be considered in been a consistent finding in patients with the Lesch- children with developmental delay and neurological Nyhan syndrome (severe HGPRT deficiency),"' but dysfunction. Autoimmune haemolytic anaemia is Arch Dis Child: first published as 10.1136/adc.62.4.385 on 1 April 1987. Downloaded from

Central nervous system dysfunction in purine nucleoside phosphorylase deficiency 391 also a recognised mode of presentation.2' The WL, Thompson LF. Watts RWE. eds. Pturine and pyrihniditne diagnosis is suggested by the finding of hypouricae- mnetabolismn in mtiani VA. New York: Plenum. 1986:481-6. Buckley RH. Schiff SE, Sampson HA, et al. Development of mia. Measurement of PNP activity and purine immunity in severe primary T cell deficiency following concentrations in body fluids will be essential to haploidentical bone marrow stem cell transplantation. confirm the metabolic basis for the defect,2' while J lInmnuntol 1986;136:2398-407. red cell GTP concentrations may be a useful guide Simmonds HA, Watson AR, Webster DR. Sahota A, Perrett D. GTP depletion and other erythrocyte abnormalities in inherited to the degree of CNS involvement. The studies also PNP deficicncy. Biochemn Pharmnacol 1982;31:941-6. indicate that there may be potential hazards as- 12 Watts RWE, Spellacy E. Gibbs DA. Allsop J, Mckeran RO, sociated with the development of PNP inhibitors Slavin GE. Clinical, post mortem, biochemical and therapeutic as immunosuppressants for different malignant observations on the Lesch-Nyhan syndrome with particular reference to the neurological manifestations. Q J Med 1982:201: states. 43-78. 13 Morris GS. Simmonds HA. Use of a fundamental elution This study was supportcd by the Medical Rcscarch Council and the protocol for the development of a reverse phase HPLC method Wellcome Trust. enabling rapid simultaneous determination of purine, pyrimi- dines and allied compounds in biological fluids. J Chromatogr 1985;344:101-13. References 14 Fairbanks LD, Goday A, Morris GS. Brolsma MFJ, Simmonds Giblett ER, Ammann AJ, Wara DW, Sandman R, Diamond HA, Gibson T. Rapid determination of purine enzyme activity LK. Nucleoside phosphorylase deficiency in a child with in intact and lysed cells using high-performance liquid chroma- severely defective T-cell immunity and normal B-cell immunity. tography with and without radiolabelled substrates. J Chromna- Lancet 1975;i:1010-3. togr 1983;276:427-32. 2 Ammann AJ. Immunological aberrations in purine nucleoside 5 Simmonds HA. Goday A, Morris GS. Fairbanks LD, Levinsky phosphorylase deficiencies. In: Enzyme defects and immune RJ. dATP accumulation and ATP depletion in platelets in dysfunction. Amsterdam: Excerpta Medica, 1979: 55-75. (Ciba adenosine deaminase deficiency: significance for the immune Foundation Symposium, No 68.) response'? Biosci Rep 1984;4:809-14. 3Stoop JW, Zegers BJM, Kuis W, et al. Purine nucleoside Ih Kaminska JE, Fox IH. Decreased S-adenosylhomocysteine phosphorylase deficiency: long-term clinical, immunological and hydrolase in inborn errors of . J Lab Cliii metabolic follow-up. In: Seligman M, Hitzig W, eds. Primary Med 1980X)9%:141-7.

immunodeficiencies. North Holland: Elsevier, 1980: 301-11. '7 Hershfield MS, Kredich NM, Ownby H, Buckley R. In vivo copyright. (INSERM Symposium 16.) inactivation of erythrocyte S-adenosylhomocysteine hydrolase 4Hirschorn R. Genetic deficiencics of adenosine deaminase and by 2' in adenosine deaminase deficient patients. purine nuclcosidc phosphorylasc: ovcrview, genetic hctcro- J Cliii Inivest 1979;63:807-11. gencity and therapy. Birth Defects 1983;19:73-81. 18 Simmonds HA, Fairbanks LD, Morris GS, Webster DR, 5Watson AR, Simmonds HA, Wcbstcr DR, Layward L, Evans Morgan G, Levinsky RJ. Correlations between purine levels, DIK. Purine nuclcosidc phosphorylasc (PNP) deficiclcy: a clinical and immunological status in ADA deficiency. In: Nyhan therapcutic challenge. In: Dc Bruyn CHMM, Simmonds HA, WL, Thompson LF, Watts RWE, eds. Purinte amid pyritnidine Muller MM, eds. Purinte metabolism in mnani IVA. New York: metabolism in mnan VA. New York: Plenum. 1986:93-101. Plenum, 1984:53-9. '9 Simmonds HA, Webster DR, Watson AR, Barratt TM, Wilson http://adc.bmj.com/ ' Zabay JM, Dc La Concha EG, Ludcna C, et al. B ccll J. Erythrocyte GTP depletion associated with severe muscular hyperactivity and abnormalitics in T cell markers and im- hypotonia in thrce inherited disorders of purine metabolism. munoregulatory function in a patient with nucleoside phos- Cliii Sci 1982;63:61. phorylase deficiency. Clin Exp l,n,nunol 1982:50:610-6. 2(1 Cohen MB, Maybaum J, Sadee W. Guanine nucleotide deple- 7Rijksen G, Zegers BJM, Spaapcn LJM, et al. Residual purinc tion and toxicity in mouse T lymphoma (S-49) cells. J Biol Chem nucleoside phosphorylasc activity in a ncw Dutch patient with 1981;256:8713-7. PNP-deficiency and cellular immunodeficiency. Peditar Res 21 Horowitz SD, Borcherding W, Hong R. Autoimmune haemo- 1986;195:772. lytic anaemia as a manifestation of T-suppressor-cell deficiency. Watson AR, Evans DIK, Marsden HB, Miller V, Rogers PA. Clin Exp Immunol 1984;33:313-23. Purine nuclcoside phosphorylase deficicncy associated with a on September 29, 2021 by guest. Protected fatal lymphoproliferative disorder. Arch Dis Child 1981 :56: Correspondence to Dr H A Simmonds, Purine Research Labora- 563-5. tory, Guy's Tower (17th and 18th Floors), Guy's Hospital, London Simmonds HA, Fairbanks LD, Morris GS, Timms P. Singh B, SE1 9RT. Bold A. Erythrocyte GTP depletion in PNP deficiency present- ing with hacmolytic anaemia and hypouricaemia. In: Nyhan Received 1 December 1986